Alpha-mercapto-gamma-butyrolactones and their preparation



United States Patent Serial No. 369,535, July 21, 1953-. Divided andthis application April 25, 1956, Serial No. 580,462

9 Claims. (Cl. 260--343.6)

' This invention relates to -[3-(l,2-dithiacyclopentyl)] V pentanoicacid. More'parti'cularl'y, it is concerned with the preparation of novela,'y [hydrocarbon substituted merc'apto] butyric acids which are usefulasintermediate-s in the synthesis of 5- [3-( l,2-dithiacyclopentyl)]pentanoic acid, and processes for preparing the same.

' This application is a division of cop'ending application Serial No.478,920, filed December 30, 1954, which latter application is in turn adivision of copending application Serial No. 369,535, filed July 21,1953.

5-[3-(1,2-dithiacyclopentyl)] pentanoic acid is a growth stimulatingcrystalline substance first isolated from liver and originally calleda-li'poic acid. This substance was found to have the structure /CH CH2(111+(CHzhCOOH and was given the common name: 6-thioctic acid, as isdisclosed in the J. Am. Chem. Soc., 74, 3455 (1952). Although5-[3-(1,2-dithiacyclopentyl)l pentanoic acid can be isolated fromnatural materi'als'such asliver, the difiiculties encountered and lowyields obtained have indicated the need for a practical synthetic methodof producing the desired product. 3

Therefore, an object of this invention is to provide novel compoundsuseful for the synthetic-production of '5-[3-(l,2-dithiacyclopentyl)]pentanoic acid. A further object is to provide processes for"preparingthese novel compounds.

According to one embodiment of the present invention novel a,'-bis[hydr'ocarbon substituted mereapto] butyric acids are providedhaving the formula: 1

wherein R is a hydrocarbon radical such as a'n'alkyl, alkenyl, aryloraralkyl groupttogether with processes and intermediates useful forpreparing the same. These compounds are useful in the synthesis of5-[3-(1,2-dithiacyclopentyD] pentanoic acid. I

The novel a,'y-bis[hydrocarbonsubstituted merca'pto] butyric acids areproduced by reacting an a,'y-dillal0 butyric acid with an ammonium,alkali metal or alkaline earth metal hydrocarbon mercaptide to form thecorresponding ammonium, alkali metal or alkaline earth metal salt of thea,y-bis[hydrocarbon substituted mercapto] butyric acid and subsequentlyhydrolyzing the salt to the corresponding u,'y-bis[hydrocarbonsubstituted mercapto] butyric acid. This reaction may be convenientlyillustrated as follows: oH2'oH;-;--oH;o0oH V YSR CH2-CH2C'HCO0YCHrOHzCH-OOO'H R" sa R I sit wherein- X is a halogen," Y is ammonium;analkali metal 2,842,558 Patented July 8, 1958 ice 2 or alkaline earthmetal, and R is a hydrocarbon radical such as an alkyl, alkenyl, aryl oraralkyl group.

The ammonium, alkali metal and alkaline earth metal salts of a -bis[hydrocarbon substituted mercapto] butyric acids are convenientyproduced by reacting the theoretical amount of about three molarequivalents of the corresponding ammonium, alkali metal or alkalineearth metal hydrocarbon mercaptide with one molar equivalent of any-dihalobutyric acid. Although this ratio of reactants has been foundmost satisfactory, other ratios including an excess of either reactantmay also'be employed if desired.

The reaction may be conveniently achieved by contacting the mercaptideand ay -dihalobutyric acid either in the presence or absence of an addedsolvent. In this regard, high yields of the desired product may beobtained by either of these methods. However, when the use of a solventis desired inert organic solvents such as chloroform, carbontetrachloride, toluene and lower alcohols may be employed withsatisfactory results. In addition, Water may be present in small amountswithout adverse effect. Temperatures from about 0 C. to about 70 C. aresuitable for effecting the reaction. However, the lower reactiontemperatures are ordinarily preferred-for effecting the reaction in thepresence of a solvent while higher temperatures are employed when thereaction is carried out in the absence of a solvent.

The reaction is completed in a relatively" short time,an hour beinggenerally sufiicient under ordinary circumstances. When the reaction hasbeen completed thecorresponding ammonium, alkali metal or alkaline earthmetal salt of a,' -bis[hydrocarb on substituted mercapto]butyric'acid'may be recovered by conventional methods or converteddirectly to the free acid according to the-succeeding step. Examples ofsalts which may be prepared according to this process from thecorresponding mercapti'des are the ammonium, sodium, potassium, lithium,calcium and magnesium salts of oc,'y-biS [methylmercapto] butyric acid,a -bisiethylmer'captol butyric acid, orgy-bis- [allylmercapto] butyricacid, u, -bis[pheny1mercapto] butyric acid, y-bisibenzylmercapto]butyric acid, and the like.

The ammonium, alkali metal and alkaline earth metal salts ofa,y-bis[hydrocarbon substituted rnercapto] butyric acids are convertedto the corresponding OtfY-blS- [hydrocarbon substituted mercapto]butyric acids by acid hydrolysis. This reaction may be convenientlyaccomplished by acidifying the reaction mixture from the previous stepwith a suitable acid, preferably a mineral acid such as phosphoric acid,hydrobromic acid, hydrochloric acid and the like. The product may thenbe isolated from the reaction mixture by conventional means such asextraction or fractional'distillation.

Illustrative of the overall process forming part of this invention isthe production of a,' -bis[methylmercapto] butyric acid by reactinga,'y-dibromobutyric acid with sodium methylmercaptide to produce sodium--ot,'ybiS [methylme'r'c'apto] butyric acid which is hydrolyzed withhydrochloric acid to a,'y-bis[methylmercapto] butyric acid. Examples ofother similar compounds which may be produced according to this processare a, y-bis[ethylmercapto] butyric acid, oi,"y-biS [propylmercapto]butyric acid, u,' -bis[butylmercapto] butyric acid,u,"y-bis[arn'ylmercaptol. butyric acid, a',' -bis[ally1rnercapto]butyric acid, c -bisl3,S-dirnethyl-Z-heptenemercaptol butyric acid,any-bis[2-methyl-l-ethyl 2-butenemercapto] butyric acid,orgy-bis[3-rnethyl-2-ethyl-2-pentenemercaptol butyric acid, u,'y-bis[phenylmercapto] butyric acid and ayybisEbenzylmercapto] butyric acid,

The a,'y-dihalobutyric acids which are used as starting materials inthis invention may be readiIy pIePared by halogenating 'y-butyrolactonewith a phosphorous trihalide action may be achieved either with orwithout the use of an added solvent. However, some solvents which may beused if desired are chloroform, carbon tetrachloride, benzene andhexane. The u,' -dihal-obutyric acid formed according to this reactionmay be used in the process of this invention as present in the reactionmixture or after its isolation therefrom by conventional methods. Withregard to the present invention best results are obtained whena,'y-dichlorobutyric acid or a,'y-dibromobutyric acid is used as thestarting material.

Examples of ammonium, alkali metal and alkaline earth metal hydrocarbonmercaptides which may be used in this invention to produce thecorresponding u,'y-bis[hydrocarbon substituted mercapto] butyric acidsare sodium methylmercaptide, magnesium ethylmercaptide, potassiumpropylmercaptide, calcium butylmercaptide, sodium phenylmercaptide,potassium benzylmercaptide, ammonium methylmercaptide, potassiumallylmercaptide, sodium 3,S-dimethyI-Z-heptenemercaptide, sodium2-methyl-1- ethyl-Z-butenemercaptide, potassium 3-methyl-2-ethyl-2-pentenemercaptide, and the like. The sodium and potassium salts of therespective mercaptides are preferred for use in the described reaction.

. Also included within the purview of this invention are the esters ofa,'y-bis[hydrocarbon substituted mercapto] butyric acids. In thisregard, alkyl, aryl and aralkyl esters may be produced by reacting an o-bis [hydrocarbon substituted mercapto] butyric acid with a halogenatingagent to form the corresponding acyl halide and subsequently reactingthe acyl halide with an alkanol, aryl alcohol or aralkanol to obtain thedesired ester. This halogenation'may be conveniently accomplished byreacting the a,'y-bis[alkyl, alkenyl, aryl or aralkyl mercapto] butyricacid, or an alkali metal salt thereof, with a suitable halogenatingagent. Examples of halogenating agents which may be used are thionylchloride, oxalyl chloride, phthalyl chloride, phosphorous trichlorideand the like. The reaction is readily achieved in a liquid medium formedby using either an excess of the halogenating agent, when liquid, or anadded inert organic solvent. Temperatures of about -10 C. are ordinarilysuitable for eflfecting the reaction although higher temperatures mayalso be used. After the reaction has been completed the tangy-bis[hydrocarbon substituted mercapto] butyryl halide is recovered accordingto the conventional procedures. Representative of the acyl halidesproduced in this manner are u,' -bis[metl1ylmercapto] butyryl chloride,a,- -bis[ethylmercaptol butyryl bromide, a,' -bis[allylmercaptol butyrylchloride and the like.

The u,'y-bis[hydrocarbon substituted mercapto] butyryl halides producesas above may be conveniently esterified by reacting the acyl halide withan excess of an alcohol corresponding to the ester desired. Thus, byreacting a,'y-bis[methylmercapto] butyryl chloride with methanol thecorresponding methyl ester is obtained. Examples of other esters whichare prepared in a like manner are ethyl-a,'y-bis[methylmercapto]butyrate, propyl-ayy-bis[ethylmercapto] butyrate, butyl-a,'-bis[propylmercapto] butyrate, methyl-aq-bis[ethylmercapto] butyrate,benzyl-ayy-bis[methylmercaptol butyrate, methyl-u,'y-bis[allylmercapto]butyrate, methyl-a -bis [phenyl-mercapto] butyrate and ethyl-a-bis[benzylmercapto] butyrate.

In addition, lower alkyl esters may also be produced by reacting anorgy-bis [hydrocarbon substituted mercapto] butyric acid with adiazoalkane, such as diazomethane or diazoethane, in a suitable dryinert solvent such as ether, chloroform, benzene and the like. Theresulting esters, like the acids, are water insoluble oils which may bepurified by distillation under reduced pressure.

. The a,'ybis[hydrocarbon substituted mercapto] butyric acids providedby this inventionare useful in the production of-[3-(1,2-dithiacyclopentyl)] pentanoic acid, also called a-lipoic acid.One such method for producing, 5.-

V [3 -(1,2-dithiacyclopentyl)] pentanoic acid, which process however, isnot part of the present invention, being the invention of Holly, Wagner,Walton and Hoffman, Serial No. 396,334 filed December 4, 1953, comprisesreacting an -bis [hydrocarbon substituted mercapto] butyryl halide witha tert.-butyl ethyl malonic acid diester methoxymagnesium derivative inan anhydrous solvent, adding water and acid to reaction mixture toconvert the resulting Grignard complex to atert.-butyl-4,6-bis[hydrocarbon substitutedmercapto]-2-carbethoxy-3-oxocaproate, treating said compound withp-toluenesulfonic acid to produce an ethyl-4,6- bis [hydrocarbonsubstituted mercapto]-3-oxocaproate, reacting said compound with methylB-chloropropionate to form a methyl-6,8- bis[hydrocarbon substitutedmercapto]-4-carbethoxy 5 oxocaprylate, deesterifying and decarboxylatingsaid compound with a mixture of glacial acetic acid and hydrochloricacid to obtain 6,8-bis[hydrocarbon substituted mercapto]-5-oxocaprylicacid, reducing said compound with sodium borohydride to thecorresponding S-hydroxy caprylic acid which immediately forms a6,8-bis[hydrocarbon substituted mercapto]-5- hydroxy caprylic acid5-lactone, reacting said lactone in glacial acetic acid containingphosphorous and iodine to produce 6,8-bis[hydrocarbon substitutedmercapto] caprylic acid and converting said compound to a-lipoic acid bydealkylation and reaction with iodine-potassium iodide. Thea,-'y-bis[hydrocarbon substituted mercapto] butyric acids which may beused according to this synthesis of a-lipoic acid are those in which thehydrocarbon substituent is an alkyl, alkenyl, aryl or aralkyl group suchas the methyl, ethyl, allyl, benzyl and phenyl radicals.

According to a further embodiment of this invention compounds having theformula crn-om-on-oooir R sn wherein R is a hydrocarbon radical such asan alkyl, aryl or aralkyl group and R is an alkyl group, may be producedaccording to an additional novel process. These compounds are alsouseful intermediates in the synthesis of 5-[3-(1,2-dithiacyclopentyl)]pentanoic acid, or a-lipoic acid.

Compounds having the described formula may be conveniently produced byreacting an OL-hElO-Y-blltYIO- lactone with an ammonium, alkali metal oralkaline earth metal hydrocarbon mercaptide to produce an oc-hYdl'O-carbon substituted mercapto-y-butyrolactone, reacting said compound withan ammonium, alkali metal or alkaline earth metal alkyl mercaptide toproduce the corresponding ammonium, alkali metal or alkaline earth metalalkyl mercaptide addition product of the OL-hYdl'OCHI'bOD. substitutedmercapto-y-butyrolactone and heating said addition compound to producethe desired product. This process may be represented structurally asfollows:

CH2CH7 CHg-CHz CHz-CHz SR SIR wherein X represents a halogen, Y isammonium, an alkali metal or alkaline earth metal and R is a hydrocarbonsuch as an alkyl, aryl or aralkyl group and R is an alkyl group.

The production of tZ-hydI'OCaI'bOH substituted mercapto-'y-butyrolactones is readily accomplished according to the first step ofthis process by reacting approximately one equivalent of ana-halo-'y-butyrolactone with about one equivalent of an. alkali metal oralkaline earth metal hy- 'drocarbon mercaptide. This reaction may beconveniently achieved by contacting the reactants in a suitable inertorganic solvent such as the lower alcohols, hexane, benzene, toluene andinert chlorinated solvents such as chloroform and carbon tetrachloride.The reaction is exothermic in nature and to prevent overheating thereactants are generally combined slowly and the mixture cooled bysuitable means. In this connection, it is preferred to maintain areactiontemperature below 60 C. to prevent destruction of the reactantsand the product. Usually an hour or so is suflicientto complete thereaction after which the product may be recoveredfrom the reactionmixture by conventional methods. One such method comprises evaporatingthe solvent and purifying the product by extraction and fractionaldistillation.

ot-Hydrocarbon substituted mercapto-yrbutyrolactones which are producedaccording to this process are a-alkyl, ,aryl and aralkylmercapto-y-butyrolactones such as u- .methylrnercapto 'y butyrolactone,a-ethylmercapto-'y butyrolactone, ot-propylmercapto 'y butyrolactone,aphenylmercapto-v-butyrolactone and a-benzylmercapto-'y- Vbutyrolactone.

The a-halo-y-butyrolactones used as starting materials inthisprocess-may be prepared by the application of .methods described in U.S. Patent No. 2,530,348 and the 2] AmaChem. 800,67, 2218 (19.45).Specifically, a chloro-y-butyrolactone and a-bromoy-butyrolactone are-;particularly suitable for this purpose.

Representative of the ammonium, alkali metal and alkaline earth metal.hydrocarbon mercaptides which may .beused as starting materials are theammonium, sodium, ;potassium, lithium, calcium and magnesium salts of-;methylmercaptan, ethylmercaptan, butylmercaptan, iphenylmercaptan andbenzylmercaptan.

Inthe'second step of this process thee-hydrocarbon substitutedmercapto-y-butyrolactones are reacted with approximately oneequivalentofa suitable ammonium, alkali metal or alkaline earth metalalkyl mercaptide to produce the corresponding-ammonium,alkalimetal or.:alkaline ,earth, metal ,alkyl -mercaptide .addition product of ,thetat-hydrocarbon substituted mercapto- -butyrolactone. This reaction isconveniently conducted in the presence of an inert non-hydroxylicsolvent such as hexane, benzene,tchloroform andthe like. The additionproduct'forms readily at ordinary. temperatures and may be recoveredfrom the reaction mixture by.removing the solvent.

Examples of addiitonal products which maybe produced in this manner arethe sodium methylmercaptide addition product ofot-rnethylmercapto-y-butyrolactone, the potassiumethylmercaptide-addition product ,of amethylmercapto- -butyrolactone,the sodium methylmercaptide addition productofa-benzyhnercapto-y-butyrolactone and the like.

Ammonium, alkali -metal and -alkaline earth metal alkyl mercaptideaddition products of a-alkyl-mercapto-y-butyrolactones maY -also beprepared according to aonestepprocGSS, rather than according to the twostep method previously described, by reacting directly abouttwo-equivalents of a suitable'ammoniurn, alkali metal or alkalineearthmetal alkyl mercaptide with one equivalent of anoc-halo-y-butyrolactone.

According 'to thisreaction the products-produced have identicalmercaptosubstituents, i. -e., -R=R', and are *therefore usefulintermediates in preparing -a, -bis 1 alkylmercapto l butyric acids.Theproduction of these addition products may be conveniently --achievedaccording to the;reaction,conditions. describedabove for theproductionof such compounds in,two,.steps.

The ammonium, alkali metal and alkaline earth metal alkyl mercaptideaddition products of a-hydrocarbon substituted-mercapto-ybutyrolactones' are converted to the corresponding oc-hydrocarbonsubstituted mercapto- 'y-alkyl mercapto-butyric acids according tothe'next stepappropriate butyrolactone addition product.

of this process by heating the addition product at an elevatedtemperature. For this purpose, temperatures of about ISO-200 C. aresatisfactory although it is preferred to effect the reaction at about170 C. At such temperatures the reaction goes to completion in about onehour. The product forms as an alkali metal or alkaline earth metal saltwhich may be conveniently recovered or hydrolyzed to the free acidwithout prior isolation by acidifying the reaction mixture to aboutpH 3with a suitable mineral acid. Recovery of the mercapto substitutedbutyric acidis achieved according to con ventional methods such asadding water to the mixture and extracting the product with a waterimmiscible inert organic solvent. By the application of'this procedurea,'y-bis[alkylmercapto] butyric acids, such as the specific examplespreviously disclosed herein, and Ot-hydIOCafbOll substitutedmercapto-y-alkylmercapto butyric acids such .asot-methylmercapto-y-ethylmercapto butyric. acid,a-ethylmercapto-y-methylmercapto butyric acid,a-phenylmercapto-v-ethylmercapto butyric acid,u-propylmercapto-yethylmercapto butyric acid andot-benZylrnercapto-ymethylmercapto butyric acid may be produced from theSalts and esters of these and similar compounds may be produced by themethods previously described herein. Furthermore, these compounds may beusedin the production of 5[3-(1,2-dithiacyclopentyl)] pentanoic acid bythe procedure referred to prior hereto.

The following examples are included to illustrate specific embodimentsof this invention.

EXAMPLE I Production of u,'y-bis[methylmercapt0] butyric acid To asolution of 77 gm. of. sodium methoxide in 750 m1. of cold anhydrousmethanol is added 100 gm. of methylmercaptan. The mixture is stirredwhile cooling by meansof an ice bath. To the resulting solution ofsodium methylmercaptide is added 105 gm. of om -dibromaintained'at about125-130 C. The temperatureiis ished pressure.

mobutyricacid. The a,' -dibromobutyric acid is added 'dropwise over aperiod of 15 minutes during which the temperature of the reactionmixture rises to about 3040 C. The reaction mixture containing thesodium salt of a,y-bis[methy1mercapto] butyric acid is concentrated to asmall volume by evaporation on a water bath under reduced pressure, 500ml. of water is added and the pH is adjusted to 3 with hydrochloricacid. The ow -bis [methylmercapto] butyric acid separates and isextracted with chloroform. The chloroform solution is extracted withaqueous sodium bicarbonate, and the bicarbonate solution is acidifiedand extracted with chloroform. The chloroform solution is dried overmagnesium sulfate and concentrated under reduced pressure to an oil. Thea,' -bis[methylmercapto] butyric acid so obtained has a refractiveindex: n =1.5276 and a neutralization equivale'ntof 183 (theory 180).

The a,'y-dibromobutyric acid is prepared as follows: 280 gm. of'y-butyrolactone and 10 ml. of phosphorous -tribromide are combined andheated to 100 C. with stirring. Bromineis addedto the mixture for about2.5 hours. During the first 1.5 hours the temperature is then lowered toC. to prevent evolution of hydrogen bromide. After the bromine additionis complete the reaction mixture is heated at 90-95 'C. for about 2hours and then cooled. The solution contains a,'y-dioromo- 1 butyricacid.

Production of methyl-u,'y.-bis[methylmercaptol butyrate ..l3.29 ;gm..ofa,'y-bis[methylmercapto] butyric acid is cooled in an ice-bath and 9.7gm. of thionyl chloride added thereto. The reaction mixture is allowedto stand overnight at ice-bath temperature and then the excess thionylchloride is removed by distillation under dimin- The residue, consistingessentially of cry-bis Emethylmercapto] butyryl chlorideiscooled in an 7ice-bath and 25 ml. of methanol is added. After the evolution of gasceases the mixture is concentrated under reduced pressure at 40 C. Theresidue, consisting of impure methyl-agy-bis[methylmercapto] butyrate isdis- I solved in ether and washed with aqueous sodium bicarbonate. Theether extract is washed with water, dried over anhydrous magnesiumsulfate, and concentrated under diminished pressure to an oil consistingof methyl-a bis [methylmercapto] butyrate.

EXAMPLE II Production of a,'y-bis[ethylmercapto] butyric acid About 15.5gm. of ethylmercaptan is added with stirring to a cold mixture of 14 gm.of potassium hydroxide in 200 ml. of ethanol. To the cold ethanolicsolution of potassium ethylmercaptide is added 21 gm. ofayy-dibromobutyric acid with stirring over a period of 1 hour. Thesolvent is removed under diminished pressure leaving a residueconsisting essentially of potassium-ow-bis[ethylmercapto] butyrate. Theresidue is added to water, acidified to pH 3 and extracted withchloroform. By evaporating the chloroform solution under diminishedpressure there is obtained u,'y-bis[ethylmercaptol butyric acid.

EXAMPLE III Production of a,'y-biS[butylmercapt0] butyric acid Asolution of sodium butylmercaptide is prepared by dissolving 27 gm. ofsodium methoxide in 300 ml. of cold methanol and adding 45 gm. ofbutylmereaptan with cooling and stirring. To the cooled solution isadded 39 gm. of a,'y-dibromobutyric acid and the mixture allowed tostand for several hours. After removing the solvent under diminishedpressure 100 ml. of water is added to the residue ofsodium-a,'y-bis[butylmercapto] butyrate. Concentrated hydrochloric acidis added to pH 3 and unreacted butylmercaptan removed by steamdistillation. The residue containing a,' -bis[1butylmercapto] butyricacid is added to chloroform and extracted with aqueous sodiumbicarbonate. The purified product is isolated by acidification of theaqueous solution,

' extraction with chloroform and removal of the solvent.

Production of ethyl-a -bisibutylmercapto] butyrate About 0.1 mole ofa,y-bis[butylmercapto] butyric acid is added slowly to 0.15 mole ofthionyl chloride.

After the reaction has terminated excess thionyl chloride is removedunder diminished pressure leaving oqy-biS- [butylmercapto] butyrylchloride. The acid chloride is cooled, combined with an excess ofethanol and warmed to 5070 C. The ethyl ester of a,'y-bis[butylmercaptolbutyric acid is isolated from the reaction mixture by removing excessethanol.

EXAMPLE IV Production of a,'y-bis[phenylmercapto] butyric acid To 250ml. of cold methanol is added 0.4 mole of sodium methylate and 0.4 moleof phenylmercaptan with stirring and cooling. About 0.13 mole ofa,'y-dibromobutyric acid is added to the cold solution of sodiumphenylmercaptide and the mixture concentrated under reduced pressure toobtain sodium-a,'y-bis[phenylmercapto] butyrate. The sodium salt isadded to 100 ml. of water and the solution is steam distilled'to removeexcess phenylmercaptan and other impurities. The residue is added towater, acidified and the a;y-bis[phenylmercapto] butyric acid extractedwith chloroform and isolated by removing the solvent.

Production of methyl-ou'y-bis[phenylmercaptol butyrate 0.2 mole of a,-bis[phenylmercapto] butyric acid and 0.3 mole of thionyl chloride arereacted under anhydrous condition at a slightly elevated temperature.Upon terimnation of the reactionthe mixture is distilled at roomtemperature under diminished pressure to remove l the methyl ester ofuyy-bis[phenylmercapto]butyric acid.

The product is isolated and purified by conventional methods.-

EXAMPLE V Production of a,'y-bis[benzlymercapto] butyric acid To asolution of 81 gm. of sodium methylate in 800 ml. of methanol is added186 gm. of benzyl-mercaptan. About 123 gm. of otyy-dibromobutyric acidis added dropwise to the mixture with cooling and stirring. The mixtureis refluxed for about one hour, the methanol removed and the residueconsisting of S0dlLlI11-ot,'yblS [benzylmercapto] butyrate added to icewater. The aqueous solution i acidified by hydrochloric acid giving a,'-bis[benzylmercapto] butyric acid as an oil. The product is purified bydissolving it in ether, extracting with aqueous potassium bicarbonate,acidifying the aqueous solution with acid and extracting the productwith ether. The purified a,'y-bis[benzylmercapto] butyric acid isrecovered by removing the ether under reduced pressure.

Production of ethylotyy-bis[benzylmercapto] butyrate Approximately 0.2mole of thionyl chloride is added to 0.15 mole of cooled a,-,-bis[benzylmercaptol butyric acid with stirring. After the initialvigorous reaction the mixture is allowed to warm to room temperature,

- stand for 1 hour and the excess thionyl chloride removed EXAMPLE VIProduction of a-methylmercapto-y-butyrolactone A solution of 20.3 gm. ofsodium methylmercaptide in 225 ml. of methanol is added to a cooledsolution of 37.7 gm. of a-bromo-y-butyrolactone in 50 ml. of methanol.After standing at room temperature for about one hour the methanol fromthe reaction mixture is distilled off under diminished pressure andreplaced with 100 ml. of water. The impurea-methylmercapto-ybutyrolacetone which separates out as an oil isextracted with chloroform. The resulting chloroform solution is washedwith water and dried over magnesium sulfate. The chloroform is removedunder diminished pressure leaving an oil which is distilled to givea-methylmercaptov-butyrolacetone boiling at 64.0-66.5" C./0.1 mm., n=1.5040. The infrared spectrum discloses a lacetone band at 5.86 ,u. andabsorption in the 13-15 a region which is indicative of the C-fiSC bond.

Production of the sodium methylmercaptide addition product ofa-methylmercapto-q-butyrolacetone is then removed by distillation togive the sodium methylmercaptide addition product ofa-methylmercapto-y-butyrolacetone.

Production of a,'y-bis[methylmercapto] butyric acid from the sodiummethylmercaptide addition product of amethylmercapto-y-butyrolactone Thesodium methylmercaptide addition product of a.-methylmercapto-v-butyrolacetone prepared above is heated at about C. forthirty minutes. After cooling the fused mixture-to about 1.00". C. itis.dissolvediin '120 ml. ofwater and the-solution adjusted to pH 3.withhydrochloric acid. The a,' .-bisfmethyhnercapto] butyric .acid separatesfrom. solutionand is extracted with chloroform. The chloroform solutionis extracted with aqueous sodium bicarbonate, the aqueous extractacidified with hydrochloric ,acid and extracted with chloroform. V Thechloroform extract is Washed with water and dried over magnesiumsulfate. The chloroform is removed by evaporation underdiminished-pressure leaving substantiallypure,.a,'y-bis[methylmercapto]butyric. acid as a heavy oil,

B. P. 154-158 C./;O .l"mm.,.n l.5267, neutralization vequivalent=l84..(theory 1:80). The infrared spectrum in carbondisulfide indicates. acarboxylic acid with a 0:0 starch at 5.85;

Production of, methykaxyis[methylmercapto] butyrate Production of thepotassium ethylmercaptide addition v product 0a-methylmercapto-y-butyrolactone A solution of 0.1 mole ofu-methylmercapto-v-butyrolactone, prepared as in Example VI, in 30 ml.of toluene is added with stirring to a suspension of 0.12 mole ofpotassium ethylmercaptide in 50 ml. of toluene. The mixture is stirredfor several hours at about 20-40 C. and the toluene removed underreduced pressure to obtain the potassium ethylmercaptide additionproduct of a-methylmercapto-'y-butyrolactone.

Production of a-methylmercapto-y-ethylmercapto butyric acid Thepotassium ethylmercaptide addition product of a-methylmercapto--butyrolactone prepared above is heated at ISO-180 C. for 45 minutes,cooled and dissolved in water. The aqueous solution ofpotassium-a-methylmercapto-y-ethylmercapto butyrate is acidified to pH 3with concentrated hydrochloric acid and extracted with chloroform. Thechloroform solution is extracted with aqueous sodium bicarbonate, theaqueous extract is acidified and finally extracted with ether. Thea-methylmercapto-y-ethylmercapto butyric acid is isolated by removingthe ether and is purified by distillation under diminished pressure.

EXAMPLE VIII Production of a-propylmercapto-y-butyrolactone To asolution of 0.3 mole of potassium propylmercaptide'in 250 ml. of ethanolis added 0.3 mole of a-bromo- 'y-butyrolactone. The reaction proceedsquickly to give a mixture containing a-propylmercapto-v-butyrolactone.The product is isolated by removing the solvent, pouring the residueinto Water, extracting with chloroform and evaporating off thechloroform. It is further purified by fractional distillation.

Production of the sodium ethylmercaptide addition product ofa-propylmercapto-y-butyrolactone The a-propylmercapto-y-butyrolactoneproduced according to the method described above is reacted with anequivalent amount of potassium ethylmercaptide in 70 ml. of toluene. Themixture is stirred overnight at room temperature and the sodiumethylmercaptide addition product of a-propylmercapto-'y-butyrolactonerecovered by distilling ofi the solvent.

t .10 Production of a-propylmercapto-y-ethylmercapto butyric acid The.sodiumethylmrtrcaptide addition product of .apropylmercapto-butyrolactone from above is fused ..at about 170 C. for about 30minutes, cooled and heated to 250 ml. of water. The aqueous solution ofsodium a-propylmercapto-y-ethylmercapto butyrate is acidified andextracted withether. .By. removing the ether there is obtaineda-propylmercapto 'y-ethylmercapto butyric acid. y

EXAMPLE IX Production of a-benzylmercapto-y-butyrolactone About 54 gm.of sodium methylate is dissolved in 400 ml. of cold methanol andcombined with a solution. of 124 gm. of benzylmercaptan-in 200ml. ofmethanol. After standingrfor 15 minutes 164 gm. of a-brOmO')butyrolactone ismadded. to -the mixture with cooling. 1 The mixture isallowed to stand at room-temperature for about one hour,: filtered andthe solventsremoved under reduced pressure. Thepresidue is added t0 '300ml. of .water, ;,extracted with chloroform ,and the :chloroform removed.The residue is distilled to giveu-benzylmercapto-v-butyrolactone, B. P.137-140 C./0.03 mm., n =1.5752.

Production of the sodium methylmercaptide addition product ofa-benzylmercapto-y-butyrolactone To a stirred solution of 0.4 mole ofot-benzylmercapto- 'y-butyrolactone in 40 ml. of toluene is added asuspension of 0.5 mole of sodium methylmercaptide in ml. of benzene. Themixture is maintained at 2040 C. for one hour and the benzene removedunder reduced pressure to give the sodium methylmercaptide additionproduct of a-benzylmercapto- -butyrolactone.

Production of a-benzlymercapto-y-methylmercapto butyric acidApproximately 0.1 mole of the sodium methylmercaptide addition productof xbenzylmercapto-v-butyrolactone is heated to 180 C. for two hours,cooled and added to water. The aqueous solution of sodium 06-benzylmercapto-y-methylmercapto butyrate is acidified, extracted withether and the ether removed to give abenzylmercapto-'y-methylmercaptobutyric acid.

EXAMPLE X Production of u,'y-bis(allylmercapto) butyric acid About 1.5moles of allyl bromide is added dropwise to a stirred refluxing solutionof 1.5 moles of thiourea in 500 ml. of methanol over a period of fifteenminutes, and refluxing is then continued for an additional thirtyminutes. A solution of three moles of potassium hydroxide in methanol isnext added rapidly and the solution refluxed for another twenty minutes.

The solution of potassium allylmercaptide thus prepared is cooled and0.5 mole of a,'y-dibromobutyric acid is added. The mixture is allowed tostand at room temperature overnight, and then concentrated under reducedpressure. The residue is diluted with water and acidified concentratedHCl. The desired product is isolated from the acidic solution byextraction with chloroform and subsequent removal of the solvent underreduced pressure. The product had the following physical constants:Neut. equiv. 247 (calc. 232.); mol. wt. (ebulliometric) 241i4 (calc.232); sulfur 25.68% (calc. 27.60%).

Production of a,'y-bis(allylmercapto) butyryl chloride A benzenesolution containing 13 g. of oi,'y-bis(allylmercapto) butyric acid iscooled in an ice bath and 5 ml. of thionyl chloride added. The mixtureis stirred with cooling for one hour, the excess thionyl chlorideremoved under reduced pressure and u, -bis(allylmercapto) butyrylchloride purified by distillation: B. P. 130-137 C./12 mm.; It =l.5456.

Production of n1ethyl-a,'y-'bis(allylmercapto) butyrate GE -CH1 CH-SRwherein R is selected from the group consisting of lower alkyl, loweralkenyl, phenyl and benzyl radicals.

. a-lower-alkylmercaptow-butyrolactone.

. a-Methylrnercapto-v-butyrolactone.

. a-Propylmercapto-y-butyrolactone.

. a-Phenylrnercapto-' -butyrolactone.

. a-Benzylmercapto-y-butyrolactone.

. The process for the production of a compound having the formulaGHQ-OH] CH-SR which comprises treating approximately one equivalent ofan u-halo- -butyrolactone with approximately one equivalent of acompound having the formula YSR, in each occurrence R being selectedfrom the group consisting of lower alkyl, lower alkenyl, phenyl andbenzyl radicals and Y a member of the group consisting of ammonium,alkali metals and alkaline earth metals.

8. The process for the production of ana-loweralkylmercapto-y-butyrolactone which comprises treatingapproximately one equivalent of an a-halo-y-butyrolactone withapproximately one equivalent of a member of the group consisting ofammonium, alkali metal and alkaline earth metal lower alkylmercaptides.

9. The process for the production of u-methylmercaptov-butyrolactonewhich comprises treating a-bromo-ybutyrolactone with sodiummethylmercaptide.

References Cited in the file of this patent

1. A COMPOUND HAVING THE FORMULA